Project Summary/Abstract The discovery that a subset of mesenchymal cells, termed ?mesenchymal stem cells (MSCs),? possesses unique self-renewal and regenerative capacities in vitro has generated immense optimism in their therapeutic potential. Despite the overwhelming enthusiasm to utilize MSCs as adoptive cellular therapy in a broad array of diseases, there is little evidence that MSCs constitute a true tissue stem cell niche in vivo, and it remains unclear if they have physiological roles in maintaining the function of their native organs. This knowledge gap has hindered the rational application of MSC therapy, and prevented insights into the role of the stroma in mediating organ function over time. We and others have recently identified a putative MSC population in adult organs that endogenously regulates tissue repair. Furthermore, we demonstrate that epithelium-secreted factors actively maintains cellular quiescence within these MSCs in the lung, providing a clue as to how the epithelium and the MSCs form a niche to maintain a slow-cycling stem cell population. Leveraging this breakthrough in the identification of putative resident MSCs, our proposal will provide definitive characterization of the resident MSC niche in the lung, and determine whether modulation of the MSC niche can impact organ function in the course of aging. The innovation of our proposal stems from the utilization of our novel mouse genetic models to determine the previously unknown long-term clonogenic and lineage potential of resident MSCs in vivo, and for the first time define the relationship between MSC aging and organ function. Understanding the physiological behavior of MSCs in vivo could provide compelling scientific rationale to improve the application of MSCs as cellular therapy. More importantly, understanding the relationship between MSCs and tissue aging could open up new therapeutic approaches to modulate endogenous MSC function in order to improve organ longevity.